Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma

被引:11
作者
Akshintala, Srivandana [1 ,8 ]
Sundby, R. Taylor [1 ]
Bernstein, Donna [1 ]
Glod, John W. [1 ]
Kaplan, Rosandra N. [1 ]
Yohe, Marielle E. [1 ,2 ]
Gross, Andrea M. [1 ]
Derdak, Joanne [1 ]
Lei, Haiyan [1 ]
Pan, Alexander [1 ]
Dombi, Eva [1 ]
Palacio-Yance, Isabel [1 ]
Herrera, Kailey R. [1 ]
Miettinen, Markku M. [3 ]
Chen, Helen X. [4 ]
Steinberg, Seth M. [5 ]
Helman, Lee J. [6 ,7 ]
Mascarenhas, Leo [6 ]
Widemann, Brigitte C. [1 ]
Navid, Fariba [6 ]
Shern, Jack F. [1 ]
Heske, Christine M. [1 ]
机构
[1] NCI, Pediat Oncol Branch, Ctr Canc Res CCR, NIH, 10 Ctr Dr, 10-CRC, Room 1-3816, Bethesda, MD 20892 USA
[2] NCI, Lab Cell & Dev Signaling, Ctr Canc Res CCR, NIH, Frederick, MD USA
[3] NCI, Lab Pathol, Ctr Canc Res CCR, NIH, Bethesda, MD USA
[4] NCI, Canc Therapy Evaluat Program CTEP, NIH, Bethesda, MD 20892 USA
[5] NCI, Biostat & Data Management, Ctr Canc Res CCR, NIH, Bethesda, MD USA
[6] Univ Southern Calif, Childrens Hosp Los Angeles CHLA, Canc & Blood Dis Inst, Keck Sch Med,Dept Pediat, Los Angeles, CA USA
[7] Osteosarcoma Inst, Dallas, TX USA
[8] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr, 10-CRC, Room 1-5750, Bethesda, MD 20892 USA
关键词
SOFT-TISSUE SARCOMA; PLACEBO-CONTROLLED PHASE-2; REFRACTORY SOLID TUMORS; OPEN-LABEL; AMG; 479; ANTIBODY CIXUTUMUMAB; MONOCLONAL-ANTIBODY; PEDIATRIC-PATIENTS; 1ST-LINE THERAPY; YOUNG-ADULTS;
D O I
10.1158/1078-0432.CCR-23-0709
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701).Patients and Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2).A 3 thorn 3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT).Results: Thirteen eligible patients, median age 18 years (range 8- 29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneu-monitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response.Conclusions: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
引用
收藏
页码:3329 / 3339
页数:11
相关论文
共 89 条
[1]   Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group [J].
Abbou, Samuel ;
Klega, Kelly ;
Tsuji, Junko ;
Tanhaemami, Mohammad ;
Hall, David ;
Barkauskas, Donald A. A. ;
Krailo, Mark D. D. ;
Cibulskis, Carrie ;
Nag, Anwesha ;
Thorner, Aaron R. R. ;
Pollock, Samuel ;
Imamovic-Tuco, Alma ;
Shern, Jack F. F. ;
DuBois, Steven G. G. ;
Venkatramani, Rajkumar ;
Hawkins, Douglas S. S. ;
Crompton, Brian D. D. .
JOURNAL OF CLINICAL ONCOLOGY, 2023, 41 (13) :2382-+
[2]   Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors [J].
Adalsteinsson, Viktor A. ;
Ha, Gavin ;
Freeman, Samuel S. ;
Choudhury, Atish D. ;
Stover, Daniel G. ;
Parsons, Heather A. ;
Gydush, Gregory ;
Reed, Sarah C. ;
Rotem, Denisse ;
Rhoades, Justin ;
Loginov, Denis ;
Livitz, Dimitri ;
Rosebrock, Daniel ;
Leshchiner, Ignaty ;
Kim, Jaegil ;
Stewart, Chip ;
Rosenberg, Mara ;
Francis, Joshua M. ;
Zhang, Cheng-Zhong ;
Cohen, Ofir ;
Oh, Coyin ;
Ding, Huiming ;
Polak, Paz ;
Lloyd, Max ;
Mahmud, Sairah ;
Helvie, Karla ;
Merrill, Margaret S. ;
Santiago, Rebecca A. ;
O'Connor, Edward P. ;
Jeong, Seong H. ;
Leeson, Rachel ;
Barry, Rachel M. ;
Kramkowski, Joseph F. ;
Zhang, Zhenwei ;
Polacek, Laura ;
Lohr, Jens G. ;
Schleicher, Molly ;
Lipscomb, Emily ;
Saltzman, Andrea ;
Oliver, Nelly M. ;
Marini, Lori ;
Waks, Adrienne G. ;
Harshman, Lauren C. ;
Tolaney, Sara M. ;
Van Allen, Eliezer M. ;
Winer, Eric P. ;
Lin, Nancy U. ;
Nakabayashi, Mari ;
Taplin, Mary-Ellen ;
Johannessen, Cory M. .
NATURE COMMUNICATIONS, 2017, 8
[3]   Drug discovery in paediatric oncology: roadblocks to progress [J].
Adamson, Peter C. ;
Houghton, Peter J. ;
Perilongo, Giorgio ;
Pritchard-Jones, Kathy .
NATURE REVIEWS CLINICAL ONCOLOGY, 2014, 11 (12) :732-739
[4]  
[Anonymous], 2010, Dasatinib. BMS-354825
[5]   Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium [J].
Aplenc, Richard ;
Blaney, Susan M. ;
Strauss, Lewis C. ;
Balis, Frank M. ;
Shusterman, Suzanne ;
Ingle, Ashish Mark ;
Agrawal, Shruti ;
Sun, Junfeng ;
Wright, John J. ;
Adamson, Peter C. .
JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (07) :839-844
[6]   Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis [J].
Bellini, Angela ;
Bernard, Virginie ;
Leroy, Quentin ;
Frio, Thomas Rio ;
Pierron, Gaelle ;
Combaret, Valerie ;
Lapouble, Eve ;
Clement, Nathalie ;
Rubie, Herve ;
Thebaud, Estelle ;
Chastagner, Pascal ;
Defachelles, Anne Sophie ;
Bergeron, Christophe ;
Buchbinder, Nimrod ;
Taque, Sophie ;
Auvrignon, Anne ;
Valteau-Couanet, Dominique ;
Michon, Jean ;
Janoueix-Lerosey, Isabelle ;
Delattre, Olivier ;
Schleiermacher, Gudrun .
CLINICAL CANCER RESEARCH, 2015, 21 (21) :4913-4921
[7]   Epitope-Specific Mechanisms of IGF1R Inhibition by Ganitumab [J].
Calzone, Frank J. ;
Cajulis, Elaina ;
Chung, Young-Ah ;
Tsai, Mei-Mei ;
Mitchell, Petia ;
Lu, John ;
Chen, Ching ;
Sun, Jilin ;
Radinsky, Robert ;
Kendall, Richard ;
Beltran, Pedro J. .
PLOS ONE, 2013, 8 (02)
[8]   Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody [J].
Cao, Liang ;
Yu, Yunkai ;
Darko, Isaac ;
Currier, Duane ;
Mayeenuddin, Linnia H. ;
Wan, Xiaolin ;
Khanna, Chand ;
Helman, Lee J. .
CANCER RESEARCH, 2008, 68 (19) :8039-8048
[9]   Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling [J].
Chaudhuri, Aadel A. ;
Chabon, Jacob J. ;
Lovejoy, Alexander F. ;
Newman, Aaron M. ;
Stehr, Henning ;
Azad, Tej D. ;
Khodadoust, Michael S. ;
Esfahani, Mohammad Shahrokh ;
Liu, Chih Long ;
Zhou, Li ;
Scherer, Florian ;
Kurtz, David M. ;
Say, Carmen ;
Carter, Justin N. ;
Merriott, David J. ;
Dudley, Jonathan C. ;
Binkley, Michael S. ;
Modlin, Leslie ;
Padda, Sukhmani K. ;
Gensheimer, Michael F. ;
West, Robert B. ;
Shrager, Joseph B. ;
Neal, Joel W. ;
Wakelee, Heather A. ;
Loo, Billy W., Jr. ;
Alizadeh, Ash A. ;
Diehn, Maximilian .
CANCER DISCOVERY, 2017, 7 (12) :1394-1403
[10]   Urine cell-free DNA multi-omics to detect MRD and predict survival in bladder cancer patients [J].
Chauhan, Pradeep S. ;
Shiang, Alexander ;
Alahi, Irfan ;
Sundby, R. Taylor ;
Feng, Wenjia ;
Gungoren, Bilge ;
Nawaf, Cayce ;
Chen, Kevin ;
Babbra, Ramandeep K. ;
Harris, Peter K. ;
Qaium, Faridi ;
Hatscher, Casey ;
Antiporda, Anna ;
Brunt, Lindsey ;
Mayer, Lindsey R. ;
Shern, Jack F. ;
Baumann, Brian C. ;
Kim, Eric H. ;
Reimers, Melissa A. ;
Smith, Zachary L. ;
Chaudhuri, Aadel A. .
NPJ PRECISION ONCOLOGY, 2023, 7 (01)